PT  - JOURNAL ARTICLE
AU  - Kratimenos, Panagiotis
AU  - Kundu, Srikanya
AU  - Ghaemmaghami, Javid
AU  - Sanidas, Georgios
AU  - Wolff, Nora
AU  - Vij, Abhya
AU  - Byrd, Chad
AU  - Simonti, Gabriele
AU  - Triantafyllou, Maria
AU  - Jablonska, Beata
AU  - Dean, Terry
AU  - Koutroulis, Ioannis
AU  - Gallo, Vittorio
TI  - Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia
AID  - 10.1523/JNEUROSCI.0899-24.2024
DP  - 2024 Oct 28
TA  - The Journal of Neuroscience
PG  - e0899242024
4099  - http://www.jneurosci.org/content/early/2024/10/28/JNEUROSCI.0899-24.2024.short
4100  - http://www.jneurosci.org/content/early/2024/10/28/JNEUROSCI.0899-24.2024.full
AB  - Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.